Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines

Definitions

• the present invention relates to a process for the separation of serotonine from coffee wax and also to processes for the preparation of certain derivatives of serotonine, more particularly N-acetyl serotonine, melatonine and mexamine.
• Serotonine the chemical name of which is 5-hydroxytryptamine, is an indolic alkaloid having the following formula: ##STR1##
• This alkaloid plays an important role in the metabolism of the brain and has vasoconstrictor, antihypertensive and antiallergenic properties, and may be used for the treatment of psychoses, migraine and for the control of excessive smoking.
• N-acetyl serotonine the chemical name of which is N-acetyl-5-hydroxytryptamine has antihypertensive properties.
• Melatonine the chemical name of which is N-acetyl-5-methoxytryptamine, is secreted by the pineal gland and possesses a regulatory activity on the circadian cycle. In addition, its use in an amount of 1-2 mg/day can induce ovulation in sheep, which is of considerable economic importance. Moreover, it has been shown that melatonine can induce sleep in man in an amount of 1-3 mg/kg body weight.
• Mexamine the chemical name of which is 5-methoxytryptamine hydrochloride, has been proposed as a sedative and as a radioprotective agent.
• the alcohol used is benzyl alcohol or one of its homologues but the yield is not increased because the alcohol forms the corresponding primary amine which is difficult to separate from the serotonine and, in addition, a ⁇ -carboline is formed from serotonine which impairs the yield.
• a much more complete hydrolysis can be achieved without provoking the formation of amines and ⁇ -carboline and leading to yield about 3.5 times greater.
• R is hydrogen or an alkyl group containing 1 to 4 carbon atoms
• x is 0 or 1
• n is an integer from 2 to 4 with the proviso that x cannot have a value of 1 when n is 3 or 4.
• Preferred solvents are ethylene glycol monobutyl ether and diethylene glycol monomethyl ether.
• the solvent has a boiling point of a least 120° C. and a melting point no higher than 30° C.
• the solvent should not substantially react with the new compounds obtained nor substantially hinder the later stages of the process and, in addition should be substantially chemically stable under drastic conditions.
• the solvent enables the water and strong base to be introduced into the lipid phase.
• the amount of solvent used may be, for instance, from 20% to 75% by weight and preferably from 30% to 50% by weight based on the weight of the coffee wax.
• serotonine is present in coffee wax in the form of amides.
• the alkaline hydrolysis breaks the amide bond and liberates the serotonine as well as the corresponding fatty acids.
• the strong base used for the hydrolysis may be, for example, sodium or potassium hydroxide.
• potassium hydroxide is preferred because it does not form solid soaps with the fatty acids which are liberated.
• the various parameters which govern the alkaline hydrolysis or saponification of the coffee wax are those conventionally used for saponification, e.g., the pH should be of the order of 12 to 14 and the amount of alkali used is advantageously from 10% to 50% by weight and preferably from 20% to 40% by weight based on the weight of coffee wax.
• the alkaline hydrolysis takes place very slowly at lower temperatures, it is preferably carried out at temperatures from 120° C. to 160° C. and especially from 130° C. to 150° C. for a time advantageously from 3 to 6 hours.
• the reaction may also take place at temperatures from 160° C. to 180° C. for a time of from 1 to 3 hours.
• the hydrolysis is desirably carried out at atmospheric pressure using from 3 to 10% preferably from 4 to 7.5% of water based on the weight of coffee wax. Amounts of water greater than 10% may be used but cause an increase in pressure and while it is possible to use amounts above about 25% there is nothing beneficial in doing so.
• the alkaline hydrolysis must be effected in an inert atmosphere, for example, under nitrogen, because serotonine is very sensitive to oxygen in an alkaline medium.
• the reaction medium is agitated vigorously.
• the coffee wax that is generally available is a by-product from the decaffeination of green coffee and therefore is rich in caffeine.
• the process according to the invention may be effected using ordinary coffee wax, it is preferred to employ decaffeinated coffee wax, because caffeine is likely to be converted into caffeidine during the alkaline hydrolysis, which lowers the yield of serotonine.
• the serotonine may be isolated from the reaction medium which contains it by conventional methods, exploiting the fact that serotonine is a compound which has basic characteristics and thus has a minimum solubility in water at pH about 10.8 (its isoelectric point).
• the present invention also provides a process for the preparation of N-acetyl serotonine characterised in that serotonine is acetylated to form N, O-diacetyl serotonine which is then treated with an alkaline mixture of water and a lower alcohol to selectively hydrolyse the O-acetyl group of the N, O-diacetyl serotonine to give N-acetyl serotonine.
• the serotonine used for the process may be obtained by any method, and may conveniently be prepared from coffee wax, preferably by the process of this invention.
• the acetylation may be carried out by conventional means, for instance, by the addition of excess acetylating agent, preferably acetic anhydride.
• the acetylation forms a mixture containing a major part of N, O-diacetyl serotonine together with a small amount of the desired N-acetyl serotonine.
• acetylated derivatives are advantageously extracted from the acetylation medium by means of a solvent substantially insoluble in water, e.g., iso-butanol, preferably at pH 7, and then conveniently concentrating the organic phase to obtain an oil containing the two acetylated derivatives.
• This oil is then selectively hydrolysed, conveniently by dissolving in an alkaline mixture of water and alcohol in an amount from 2.5 to 7.5 times the volume of oil, preferably at a pH above 11 to produce the N-acetyl serotonine.
• the alcohol preferably has a boiling point below 100° C. and conveniently contains from 1 to 4 carbon atoms and is conveniently methanol, ethanol, n-propanol or isopropanol.
• the selective hydrolysis may conveniently be carried out a temperature from 15° C. to 50° C., preferably from 25° C. to 40° C., over a suitable period of time, for instance from 15 to 60 minutes.
• the pH may be adjusted by the addition of 30% sodium hydroxide solution.
• the present invention further provides a process for the preparation of melatonine characterised in that N-acetyl serotinone is methylated in the 5-position.
• Any conventional methylating agent may be used, especially dimethyl sulphate which may, for instance, be added in excess to the aqueous-alcoholic solution of N-acetyl serotonine prepared as hereinbefore described.
• the pH is preferably above 11 and may be adjusted by adding a 30% sodium hydroxide solution while the temperature preferably does not exceed 45° C.
• melatonine crystallises and may be separated mechanically, e.g., by filtration after which the reaction medium may be extracted, by conventional means, with a suitable solvent to recuperate the remainder of the melatonine.
• solvents that may be used are dichloromethane, chloroform, isobutanol and higher alcohols, ethyl acetate and some fluoro-chloro alkanes e.g. Freons, Halons.
• the present invention also provides a process for the production of mexamine characterised in that melatonine is deacetylated in a hot alkaline solution containing a substantially water-insoluble alcohol and then washed with water after which the alcohol phase is separated from the aqueous phase and acidified with hydrochloric acid.
• reaction mixture is cooled, for instance to ambient temperature, before washing with water.
• the hot alkaline solution preferably contains sodium hydroxide and the temperature is conveniently above 90° C., and desirably at reflux.
• the alcohol preferably contains from 4 to 8 carbon atoms and may be, for example, isobutanol, a pentanol, a hexanol or a benzyl alcohol. After washing with water the alcohol phase is preferably acidified to a pH of less than 3 and then, if desired, concentrated.
• the mexamine crystallises and may be separated by conventional means. The mexamine is advantageously prepared from melatonine produced as hereinbefore described in accordance with the present invention.
• Example 2 To the aqueous solution of serotonine obtained in Example 1, there were added 40 g acetic anhydride while maintaining the pH between 8-9 with 30% sodium hydroxide at 25° C. to 30° C. N, O-diacetyl serotonine formed, having the appearance of an insoluble gum, and was extracted twice with 500 g isobutanol. The extract thus obtained was concentrated to obtain 80 g of an oil which was dissolved in a mixture containing 320 parts water and 80 parts ethanol. The pH was adjusted to 12.5 with 30% sodium hydroxide and the solution maintained at about 30° C. for 30 minutes, which provokes the selective hydrolysis of the O-acetyl group. The solution then contained 36 g N-acetyl serotonine.
• the melatonine obtained in Example 3 was taken up in 300 g isobutanol. To this mixture were added 30 g sodium hydroxide and 3 g of sodium dithionite and the whole mixture was refluxed at 105° C. for 2 hours under nitrogen. The reaction mixture was then cooled and extracted with 500 g water. The aqueous phase which contained sodium acetate formed as well as excess sodium hydroxide, was separated. The isobutanol phase was acidified to pH 2 with 32% hydrochloric acid and then concentrated which induced the crystallisation of the mexamine which was then filtered. 36 g of crude mexamine was thus obtained. After recrystallisation in 96% ethanol, 30 g of white crystals of mexamine were obtained having a purity of 98.5%.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)
• Steroid Compounds (AREA)
• Compounds Of Unknown Constitution (AREA)
• External Artificial Organs (AREA)
• Treatment Of Liquids With Adsorbents In General (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Peptides Or Proteins (AREA)

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• 1983
  • 1983-07-01 US US06/510,167 patent/US4506080A/en not_active Expired - Lifetime
• 1984
  • 1984-04-26 EP EP84104696A patent/EP0130303B1/fr not_active Expired
  • 1984-04-26 AT AT86103841T patent/ATE38513T1/de not_active IP Right Cessation
  • 1984-04-26 DE DE8484104696T patent/DE3462794D1/de not_active Expired
  • 1984-04-26 EP EP86103842A patent/EP0197390B1/fr not_active Expired
  • 1984-04-26 EP EP86103841A patent/EP0197389B1/fr not_active Expired
  • 1984-04-26 AT AT86103842T patent/ATE38514T1/de not_active IP Right Cessation
  • 1984-05-02 GB GB08411197A patent/GB2142622B/en not_active Expired
  • 1984-05-03 IL IL71737A patent/IL71737A/xx unknown
  • 1984-05-23 ZM ZM33/84A patent/ZM3384A1/xx unknown
  • 1984-05-24 JP JP59103799A patent/JPS6025966A/ja active Granted
  • 1984-06-29 OA OA58329A patent/OA07734A/fr unknown
  • 1984-06-30 ES ES533890A patent/ES533890A0/es active Granted
• 1985
  • 1985-07-16 ES ES545230A patent/ES545230A0/es active Granted
  • 1985-07-16 ES ES545232A patent/ES545232A0/es active Granted
  • 1985-07-16 ES ES545231A patent/ES8604142A1/es not_active Expired
  • 1985-08-29 GB GB08521543A patent/GB2165837B/en not_active Expired
  • 1985-08-29 GB GB08521544A patent/GB2165838B/en not_active Expired
• 1988
  • 1988-07-12 JP JP63171969A patent/JPS6445361A/ja active Granted
  • 1988-07-12 JP JP63171971A patent/JPS6445363A/ja active Granted
  • 1988-07-12 JP JP63171970A patent/JPS6445362A/ja active Granted

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